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The Double-Sided Effects of Mycobacterium Bovis Bacillus Calmette–Guérin Vaccine ✉ ✉ Junli Li 1,2,3,4, Lingjun Zhan1,2,3,4 and Chuan Qin 1,2,3,4

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The Double-Sided Effects of Mycobacterium Bovis Bacillus Calmette–Guérin Vaccine ✉ ✉ Junli Li 1,2,3,4, Lingjun Zhan1,2,3,4 and Chuan Qin 1,2,3,4 www.nature.com/npjvaccines REVIEW ARTICLE OPEN The double-sided effects of Mycobacterium Bovis bacillus Calmette–Guérin vaccine ✉ ✉ Junli Li 1,2,3,4, Lingjun Zhan1,2,3,4 and Chuan Qin 1,2,3,4 Bacillus Calmette–Guérin (BCG), the only vaccine proven to be effective against tuberculosis (TB), is the most commonly used vaccine globally. In addition to its effects on mycobacterial diseases, an increasing amount of epidemiological and experimental evidence accumulated since its introduction in 1921 has shown that BCG also exerts non-specific effects against a number of diseases, such as non-mycobacterial infections, allergies and certain malignancies. Recent Corona Virus Disease 2019 (COVID-19) outbreak has put BCG, a classic vaccine with significant non-specific protection, into the spotlight again. This literature review briefly covers the diverse facets of BCG vaccine, providing new perspectives in terms of specific and non-specific protection mechanisms of this old, multifaceted, and controversial vaccine. npj Vaccines (2021) 6:14 ; https://doi.org/10.1038/s41541-020-00278-0 INTRODUCTION infections observed in children after receiving BCG vaccina- 17–20 Bacillus Calmette–Guérin (BCG), a live-attenuated bacterial tion . Clinical evidence also suggests that BCG may be 1234567890():,; effective against infections caused by viral pathogens, such as vaccine derived from Mycobacterium bovis was originally – 1 respiratory syncytial virus21,22, human papilloma virus23 25,and isolated in 1902 from a cow with tuberculosis (TB) .Theisolate 26 was cultured continuously for >230 generations for 13 years herpes simplex virus . Moreover, an increasing number of (1908–1921) to generate a mutant strain with weakened animal studies using mouse models have demonstrated the virulence but with high immunogenicity2. First used in humans effects of BCG on secondary viral infections. In two separate studies, mice immunized with BCG have been shown to exhibit a in 1921, BCG vaccine has been included in the infant fi fl immunization programs by the World Health Organization signi cantly lower titer of in uenza A virus (H1N1), resulting in a decreased level of inflammation and lung injury, compared with (WHO) since 1974. As of 2018, BCG has been used within the 27,28 national vaccination program of 180 countries or territories in those without BCG immunization . Furthermore, other studies have reported that BCG-vaccinated animal models or Asia, Africa, Europe, and America, with a coverage range of over 3–5 humans appeared to be more resistant to various viruses, 90% . Since the 1920s, the original BCG strain has been – including herpes simplex virus types 1 and 229 31,sendaivirus32, shipped to 20 different international sites, where the vaccine Japanese encephalitis virus33, encephalomyocarditis virus34,35, was repeatedly sub-cultured under different conditions. This has and ectromelia virus36,37, or to non-communicable diseases, given rise to diverse licensed BCG formulations that are distinct 38 39 40 6–8 such as leukemia , allergy , and childhood diabetes . in live mycobacteria content and in genetic composition . Remarkably,BCGcanbeusedasanexpressionvectorfor Currently, the most widely used strains for BCG vaccine recombinant antigens to develop novel vaccines for pathogenic production globally include French Pasteur strain (Pasteur bacteria and viruses41–45,aswellasforcancerimmunother- 1173P2), Denmark 1331 strain (Danish 1331), Brazil strain (BCG apy38,46,47. Clearly, BCG cannot be regarded as a vaccine with Mearou RJ), Russian strain (Moscow-368), Bulgarian substrain only “SpecificEffects” for unilateral prevention of TB. Hence, 9,10 (Sofia SL222), and the Japan 172 strain (Tokyo 172-1) . further understanding on the possible “NSEs” of BCG is As one of the oldest and most widely used vaccines in the required. world, BCG has been administered for nearly a century, with more than four billion of BCG-vaccinated individuals globally11. In most countries, BCG is administered to newborns a few hours CLINICAL CHARACTERIZATION OF BCG VACCINATION or days after birth, and it has been shown to exhibit a protective The safety of BCG has remained as the primary concern regardless efficacy of 73% and 77%, respectively, against TB meningitis and of whether it is used for immune prevention or immunotherapy48. 12–16 miliary TB . Although BCG was specifically developed as a Adverse reactions in children owing to BCG vaccination have been vaccine for TB, numerous studies have shown that BCG has the well reported in countries that routinely administer BCG49. ability to induce the so-called Non-Specific Effects (NSEs) that Complications arising from BCG vaccination can be either mild provide effective protection against other infectious diseases. or severe50. Immune-compromised individuals with conditions Several epidemiological studies conducted in TB endemic such as severe comprehensive immune deficiency, cellular countries have demonstrated that immunization of neonates immune deficiency, chronic granulomatous disease, IL-12 and with BCG can lower neonatal mortality by 50%17, which may be IFN-γ-mediated immune impairment51 often show more-severe attributed to the decreased likelihood of sepsis and respiratory reactions to BCG vaccine, and should therefore avoid BCG 1NHC Key Laboratory of Human Disease Comparative Medicine, Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing 100021, P.R. China. 2Beijing Key Laboratory for Animal Models of Emerging and Reemerging Infectious, Beijing 100021, P.R. China. 3Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Beijing 100021, P.R. China. 4Tuberculosis Center, Chinese Academy of Medical Sciences (CAMS), ✉ Beijing 100021, P.R. China. email: [email protected]; [email protected] Published in partnership with the Sealy Institute for Vaccine Sciences J. Li et al. 2 vaccination. Other factors that may contribute to the development internalized by DCs can live up to 2 weeks inside these cells68, of adverse reactions include evaluation criteria employed, potency triggering the upregulation of costimulatory molecules and the and dosage of the vaccine strain used, number of immunization production of immune-polarizing cytokines, which are charac- applied, route of delivery, age and immune status of the terized by an increased expression level of CD40, CD80, CD83, vaccinated individual and the skills of the operator administering and CD8669,70. On the other hand, BCG can be phagocytosed the vaccine. and degraded by macrophages, giving rise to immunogenic components of BCG cell wall skeleton, including covalently 66 Normal reactions to BCG vaccination linked mycolic acid, arabinogalactan, and peptidoglycan that can strongly stimulate an inflammatory response through the BCG, as a live bacterial vaccine, can inevitably disseminate beyond 69,71–73 the vaccination site and regional lymph nodes to various parts of activation of different pattern recognition receptors (PRRs) . During the recognition of BCG, whilst the signaling of Toll-like the body under certain conditions. About 2 weeks after BCG receptor (TLR) 2 is triggered via mycobacterial cell wall lipoglycans vaccination, an indurated area with an average diameter of and lipids, such as lipomannan (LM); the signaling of TLR4 ~10 mm typically occurs at the injection site, followed by redness, triggered via other mycobacterial proteins, such as multiple heat- swelling, suppuration, and spontaneous ulceration, which turns – shock proteins and glycoproteins66,74 77. It has been shown that into a crust that falls off on its own after healing in ~6–12 weeks, BCG CpG-DNA can activate intracellular TLR9 in DCs and forming a small permanent scar, commonly known as the “BCG macrophages, resulting in cell activation and the production of Scar”. It takes about 2 or 3 months after BCG vaccination to IL-12, TNF-α, and MCP-1, a crucial mediator of Th1 immune develop a “BCG Scar” without any systemic adverse reactions. It is – response78 82. Likewise, complement receptors CR3 and CR4, worth noting that a small number of individuals receiving BCG nucleotide-binding oligomerization domain (NOD)-like receptors vaccination have been reported to result in slight swelling of the and C-type lectins have been shown to interact with bacterial cell axillary lymph nodes on the same side of the vaccination site52. wall components and participate in the recognition and Generally speaking, the reactions described above are normal 71,83,84 internalization of BCG . Furthermore, studies on BCG- after BCG vaccination, which are self-limiting without requiring immunized adults have demonstrated reprogramming of mono- any special medical treatment. cyte precursors with higher expression of PRRs and greater reactivity to stimuli, such as TLR agonists. Adverse reactions to BCG vaccination 1234567890():,; BCG is the most widely used vaccine globally with an excellent Adaptive immune protection overall safety record. Adverse reactions and complications after Antigen-presenting cells such as DCs, macrophages, and B cells BCG vaccination mainly include mild and transient fever (that – 53 present BCG-derived antigen peptides to major histocompat- alleviates spontaneously after 1 2 days), injection site abscesses ibility complex (MHC) molecules and primary T cells located in (with a diameter of >10 mm that heal in >12 weeks), lymphade- 54 the nearest secondary lymphoid tissue or spleen to initiate an nitis,
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